The present invention relates to B-group streptogramin compounds of formula (I): 
as well as the salts thereof, which exhibit antibacterial activity alone or in combination with an A-group streptogramin compound.
Among the known streptogramins, pristinamycin (RP 7293), an antibacterial agent of natural origin produced by Streptomyces pristinaespiralis, was isolated for the first time in 1955. The pristinamycin sold under the name Pyostacine(copyright) comprises mainly pristinamycin IA combined with pristinamycin IIA.
Another antibacterial agent of the streptogramin family, virginiamycin, was isolated from Streptomyces virginiae, ATCC 13161 (Antibiotics and Chemotherapy, 5, 632 (1955)). Virginiamycin (Staphylomycine(copyright)) comprises mainly factor S combined with factor M1.
Semisynthetic derivatives of streptogramins represented by formula (A): 
wherein:
Ra is a radical of structure xe2x80x94CH2Rxe2x80x2a for which Rxe2x80x2a is a radical of the heterocyclylthio type which may be substituted, or alternativeiy represents a radical of structure xe2x95x90CHRxe2x80x2a for which Rxe2x80x2a is a substituted alkylamino, alkyloxy or alkylthio radical, or a radical of the heterocyclylamino, heterocyclyloxy or heterocyclylthio type which may be substituted, Rb and Rc are hydrogen atoms and Rd is a hydrogen atom or a dimethylamino radical, or alternatively Ra is a hydrogen atom and Rb is hydrogen or methyl, and Rc and Rd are hydrogen or various substituents, have been described in European Patent Nos. EP 133 097, EP 248 703, EP 770 132, and EP 772 630.
When combined with a semisynthetic component of the streptogramin A group, they can show synergistic action and can be used as antibacterial agents, administered either via injection or orally.
European Patent No. EP 133 098 also discloses B-group synergistin derivatives bearing aminomethylenyl chains in position 5xcex4, which are synthetic intermediates.
It has now been found, in accordance with the present invention, that the compounds of formula (I), wherein:
R is chosen from xe2x80x94NR1R2 and xe2x80x94SR3, wherein:
R1 and R2, which may be identical or different, are independently chosen from a hydrogen atom and the radicals:
alkyl(1 to 8 carbons), which are unsubstituted or substituted with hydroxyl;
alkenyl (3 to 8 carbons);
cycloalkyl (3 to 8 carbons);
alkyloxy (1 to 8 carbons);
dialkylamino;
phenylalkyl, which is unsubstituted or substituted with one or more halogen atoms or radicals chosen from alkyl, hydroxyalkyl, alkyloxy, and dialkylamino;
saturated and unsaturated heterocyclylalkyl (3- to 8-membered) containing one or more hetero atoms chosen from nitrogen, sulphur and oxygen; and dialkylaminoalkyl;
or, alternatively,
R1 and R2, together with the nitrogen atom to which they are attached, form a ring chosen from 3- to 12-membered, saturated, partially saturated, and unsaturated, monocyclic and polycyclic heterocycles optionally containing at least one additional hetero atom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted with one or more radicals chosen from:
hydroxyl;
alkyl;
phenyl, which is unsubstituted or substituted with a halogen atom;
phenylalkyl;
phenylalkenyl (alkenyl containing 2 to 4 carbons);
hydroxyalkyl;
acyl;
alkyloxycarbonyl; and
heterocyclyl and heterocyclylcarbonyl, wherein the heterocyclyl portion is saturated or unsaturated (4- to 6-membered) and contains one or more hetero atoms chosen from oxygen, sulphur, and nitrogen;
R3 is chosen from:
alkyl (containing 1 to 8 carbons) and cycloalkyl (containing 3 to 8 carbons) radicals, both of which are substituted with a radical chosen from:
xe2x80x94NR1R2, wherein R1 and R2, which may be identical or different, are chosen from:
a hydrogen atom; and
alkyl radicals;
or form, together with the nitrogen atom to which they are attached, a heterocycle as defined above;
or, alternatively,
R3 is chosen from 3- to 7-membered, saturated and unsaturated, monocyclic and polycyclic, heterocyclyl and heterocyclylmethyl radicals optionally containing at least one additional hetero atom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted with at least one alkyl radical; 
xe2x80x83represents an unsaturated ring residue which is unsubstituted at 5xcex3: 
xe2x80x83or a saturated ring residue which is substituted at 5xcex3 with a fluoro radical: 
Ra is chosen from methyl and ethyl radicals; and
Rb, Rc, and Rd have the following definitions:
1) Rb and Rc are both a hydrogen atom; and
Rd is chosen from a hydrogen atom and methylamino and dimethylamino radicals;
2) Rb is a hydrogen atom;
Rc is chosen from hydrogen, chlorine, and bromine atoms, and alkenyl radicals (3 to 5 carbons); and Rd is a radical xe2x80x94NMexe2x80x94Rxe2x80x2xe2x80x3, wherein Rxe2x80x2xe2x80x3 is chosen from:
alkyl, hydroxyalkyl (2 to 4 carbons), and alkenyl (2 to 8 carbons) radicals, which are unsubstituted or substituted with at least one radical chosen from:
phenyl;
cycloalkyl (3 to 6 carbons);
methyl;
benzyl; and
substituted benzyl, wherein one or more substitutents are chosen from:
xe2x80x83halogen atoms and hydroxyl, alkyl, alkyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, amino, alkylamino and dialkylamino radicals; and
heterocyclylmethyl and heterocyclylethyl, wherein the heterocyclyl portion is saturated or unsaturated and 5- or 6-membered and contains 1 or 2 hetero atoms chosen from sulphur, oxygen, and nitrogen, and which are unsubstituted or substituted with one or more radicals chosen from:
alkyl, alkenyl (2 to 8 carbons), cycloalkyl (3 to 6 carbons), saturated and unsaturated 4- to 6-membered heterocyclyl, phenyl, substituted phenyl as defined above for the definition of R1, and benzyl radicals;
or, alternatively,
Rxe2x80x2xe2x80x3 is chosen from cyanomethyl, carboxymethyl, xe2x80x94CORe and xe2x80x94CH2CORe radicals, wherein Re is xe2x80x94ORxe2x80x2e, and wherein Rxe2x80x2e is chosen from:
alkyl (1 to 6 carbons);
alkenyl (2 to 6 carbons);
benzyl;
phenyl;
tolyl; and
heterocyclylmethyl radicals, wherein:
the heterocyclyl portion is 5- or 6-membered and contains 1 or 2 hetero atoms chosen from sulphur, oxygen and nitrogen;
or, alternatively,
Re is chosen from:
alkylamino;
alkylmethylamino; and
heterocyclylamino and heterocyclylmethylamino radicals, wherein:
the heterocyclyl radical is saturated and 5- or 6-membered and contains 1 or 2 hetero atoms chosen from sulphur, oxygen, and nitrogen, and is unsubstituted or substituted with a radical chosen from alkyl, benzyl, and alkyloxycarbonyl radicals;
3) Rb is a hydrogen atom;
Rd is chosen from xe2x80x94NHCH3 and xe2x80x94N(CH3)2 radicals; and Rc is chosen from chlorine and bromine atoms, and from alkenyl radicals (3 to 5 carbons) when Rd is xe2x80x94N(CH3)2;
4) Rb and Rd are both a hydrogen atom; and
Rc is chosen from halogen atoms and alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, alkyl (1 to 6 carbons), and trihalomethyl radicals;
5) Rb and Rc are both a hydrogen atom; and
Rd is chosen from halogen atoms and ethylamino, diethylamino, methylethylamino, alkyloxy, trifluoromethoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkyl (1 to 6 carbons), phenyl, and trihalomethyl radicals;
6) Rb is a hydrogen atom;
Rc is chosen from halogen atoms and alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, and alkyl (1 to 3 carbons) radicals; and
Rd is chosen from halogen atoms and amino, alkylamino, dialkylamino, alkyloxy, trifluoromethoxy, thioalkyl, alkyl (1 to 6 carbons), and trihalomethyl radicals; and
7) Rc is a hydrogen atom; and
Rb and Rd are both methyl radicals; show particularly advantageous activities for treating infections when administered orally and/or parenterally.
The streptogramin compounds of formula (I) may exhibit powerful oral and parenteral activity, which makes them extremely useful for treating serious infections, for example, in a hospital environment via injection, which administration may be followed by an oral ambulatory treatment which is easier to administer to the patients. Thus, the practitioner is no longer obliged to change the patient""s category of medicinal product between the end of the hospital treatment and the overall end of the treatment.
In the formula (I) above, the halogen atoms can be chosen from fluorine, chlorine, bromine, and iodine; the alkyl and acyl radicals are straight or branched and, except where specifically mentioned, may contain from 1 to 4 carbon atoms. The alkenyl radicals can also be in the form of a straight or branched chain, and can contain from 2 to 4 carbon atoms.
It is also understood that, in the above definitions, when R1 and R2 represent heterocyclylalkyl, they comprise a heterocyclyl radical or form a heterocycle together with the nitrogen atom to which they are attached, or when R3 represents a heterocyclyl or heterocyclylmethyl radical, wherein the heterocyclyl portion of the radical can be saturated or unsaturated and optionally polycyclic, such as, for example, bicyclic or tricyclic.
Among the heterocyclyl radicals mentioned above, those which may be mentioned include, for example, pyrrolyl, pyrrolidinyl, piperidinyl, pyrazinyl, pyrimidinyl, piperazinyl, pyridyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl, morpholinyl, thiomorpholinyl, thiazolyl, oxazolyl, imidazolidinyl, imidazolyl, benzimidazolyl, furyl, thienyl, and dioxolanyl radicals.
According to one aspect of the invention, the compounds of formula (I) can be prepared by the action of a fluorinating agent on the B-group synergistin compound of formula (II): 
wherein R, Ra, Rb, Rc, and Rd are defined as above, followed by separation of the fluoro derivative or of the derivative which is unsaturated in the 5xcex3-5xcex4 position.
The reaction is generally performed by the action of a fluorinating agent such as a sulphur fluoride, for example, aminosulphur trifluoride: morpholinosulphur trifluoride, diethylaminosulphur trifluoride (Tetrahedron, 44, 2875 (1988), bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor(copyright)) or, for example, sulphur tetrafluoride (J. Org. Chem., 40, 3808 (1975), the disclosures of which are incorporated herein by reference, or an agent such as hexafluoropropyldiethylamine (Japanese Patent No. JP 2 039 546, the disclosure of which is incorporated herein by reference) or N-(2-chloro-1,1,2-trifluoroethyl)diethylamine. The reaction can be performed in an organic solvent such as, for example, a chlorinated solvent, such as dichloromethane, dichloroethane, or chloroform, at a temperature ranging from xe2x88x9270xc2x0 C. to 50xc2x0 C. and in an inert medium, for example, under argon or nitrogen.
The fluoro derivative and the unsaturated derivative wherein: 
represents: 
are separated according to the usual methods which do not adversely affect the rest of the molecule, for example, by performing a chromatography or a crystallization.
According to another aspect of the invention, the synergistin compounds of formula (I), wherein 
represents: 
can be prepared by the action of a thionyl halide, in the presence of a nitrogenous base, on the B-group synergistin compound of formula (II).
The reaction is performed by treating thionyl chloride or bromide in the presence of a nitrogenous base such as, for example, triethylamine or pyridine at a temperature ranging from xe2x88x9250xc2x0 C. to +80xc2x0 C., in a chlorinated solvent such as, for example, dichloromethane, 1,2-dichloroethane, or chloroform, or an ether such as, for example, tetrahydrofuran (THF).
The B-group synergistin compounds of formula (II) can be prepared by reducing the 5xcex3 ketone function of a streptogramin compound of formula (III): 
wherein R, Ra, Rb, Rc, and Rd are defined as above, according to the usual methods which do not adversely affect the rest of the molecule.
The process is performed by treatment with a reducing agent such as a hydride, for example an alkaline borohydride such as, for example, sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride, at a temperature ranging from xe2x88x9270xc2x0 C. to 60xc2x0 C., in an organic solvent such as an ether, for example, THF, or an alcohol, for example, methanol or ethanol, or a chlorinated solvent, for example, dichloromethane.
The streptogramin compound of formula (III) can be prepared according to, or by analogy with, the methods described in European Patent Nos. EP 133 097, EP 133 098, EP 248 703, EP 432 029, EP 770 132, and EP 772 630, the disclosures of which are incorporated herein by reference.
According to the invention, the streptogramin compounds of formula (I) wherein the symbol 
represents 
can also be prepared by the action of an amine HNR1R2 or a thiol HSxe2x80x94R3 on a halogenated streptogramin compound of formula (IV): 
wherein Ra, Rb, Rc, and Rd are defined as above, and Hal represents a halogen atom.
According to certain embodiments, the symbol Hal represents a chlorine or bromine atom.
The reaction of the amines R1R2NH is performed in an organic solvent such as an amide, for example, dimethylformamide, or a nitrite, for example, acetonitrile, or a chlorinated solvent, for example, chloroform, at a temperature ranging from 0xc2x0 C. to 80xc2x0 C. The process is optionally performed in the presence of triethylamine. When a thiol HSxe2x80x94R3 is reacted, the process is performed in basic medium, for example, in the presence of an alkaline hydride, for example, sodium hydride, in an organic solvent such as an amide, for example, dimethylformamide, or a nitrite, for example, acetonitrile, optionally in the presence of triethylamine, at a temperature ranging from 0xc2x0 C. to 80xc2x0 C.
The streptogramin compounds of formula (IV) can be prepared by treating a 5xcex4-methylene streptogramin of formula (V): 
wherein Ra, Rb, Rc, and Rd are defined as above, with a halogenating agent.
The process can be performed using common halogenating agents which do not adversely affect the rest of the molecule. For example, thionyl chloride or bromide is reacted in an organic solvent such as a chlorinated solvent, for example, dichloromethane, dichloroethane, or chloroform, or an ether, for example, tetrahydrofuran, or the process is performed in a mixture of these solvents, at a temperature ranging from xe2x88x9260xc2x0 C. to 80xc2x0 C.
The streptogramin compounds of formula (V) can be prepared by reducing the 5xcex3 ketone function of a synergistin compound of formula (VI): 
wherein Ra, Rb, Rc, and Rd are defined as above.
The reaction is performed under conditions similar to the conditions described for obtaining a streptogramin compound of formula (II) from a compound of formula (III). The process may be performed in an organic solvent such as an alcohol, for example, methanol, or a chlorinated solvent, for example, dichloromethane, dichloroethane, or chloroform, or in a mixture of alcoholic solvent/chlorinated solvent, for example, methanol/dichloromethane, in the presence of anhydrous cerium chloride, at a temperature ranging from xe2x88x9260xc2x0 C. to 60xc2x0 C.
The streptogramin compounds of formula (VI) can be prepared according to the methods described in European Patent Nos. EP 133 098 and EP 432 029, or by analogy with these methods, or the methods described in European Patent Nos. EP 248 703, EP 770 132, EP 772 630, EP 821 697, and International Patent Application No. WO 99/43699, the disclosures of which are all incorporated herein by reference, as well as the methods described hereinbelow in the examples.
The streptogramin compounds of formula (I) or (IV) can be purified, if necessary, by physical methods such as crystallization or chromatography.
The streptogramin compounds of formula (II), wherein R, Ra, Rb, Rc, and Rd are as defined above, are novel compounds. It is understood that these compounds also fall within the scope of the present invention.
Some of the streptogramin compounds of formula (I) can be converted into the form of addition salts with acids, by known methods. It is understood that these salts are also part of the present invention. As examples of addition salts with pharmaceutically acceptable acids, mention may be made of the salts formed with inorganic acids such as, for example, hydrochlorides, hydrobromides, sulphates, nitrates, and phosphates, or with organic acids such as, for example, succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulphonates, ethanesulphonates, phenylsulphonates, p-toluenesulphonates, isethionates, naphthalenesulphonates, or camphorsulphonates, or with substitution derivatives of these compounds.
Where appropriate, the compounds bearing a carboxyl substituent may be converted into metal salts or into addition salts with nitrogenous bases according to the methods that are known per se. These salts can be obtained by the action of a metallic base, for example, alkali metal or alkaline-earth metal bases, ammonia, or an amine on a compound according to the invention, in a suitable solvent such as an alcohol, an ether, or water, or by exchange reaction with a salt of an organic acid. The salt formed precipitates after optionally concentrating the solution, and is separated out by filtration, settling, or lyophilization. Examples of pharmaceutically acceptable salts which may be mentioned include the salts with alkali metals such as, for example, sodium, potassium, and lithium, or with alkaline-earth metals such as, for example, magnesium or calcium, the ammonium salt, the salts of nitrogenous bases such as, for example, ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-xcex2-phenethylamine, N,Nxe2x80x2-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, or dibenzylamine.
The streptogramin compounds according to the present invention may have antibacterial properties and synergizing properties with respect to the antibacterial activity of the A-group streptogramin compounds. They may be useful on account of their activity, alone or in combination with A-group streptogramin components. They may also be useful on account of their activity, both orally and parenterally, which opens the way to an ambulatory relay treatment without modifying the nature of the medicinal product.
When they are combined with an A-group streptogramin component or derivative, these components or derivatives can be chosen, depending on whether it is desired to obtain a form for oral or parenteral administration, from the following natural components: pristinamycin IIA, pristinamycin IIB, pristinamycin IIC, pristinamycin IID, pristinamycin IIE, pristinamycin IIF, and pristinamycin IIG, or from semisynthetic derivatives as described in U.S. Pat. No. 4,590,004 and European Patent No. EP 191 662, the disclosures of which are incorporated herein by reference, or alternatively from the semisynthetic compounds of formula (xcex1): 
described in International patent application WO 99/051265, the disclosure of which is incorporated herein by reference, wherein R1 is a radical xe2x80x94NRxe2x80x2Rxe2x80x3 for which Rxe2x80x2 is a hydrogen atom or a methyl radical, and Rxe2x80x3 is a hydrogen atom or an alkyl, cycloalkyl, allyl, propargyl or benzyl radical or a radical xe2x80x94ORxe2x80x3xe2x80x2, Rxe2x80x3xe2x80x2 being a hydrogen atom or an alkyl, cycloalkyl, allyl, propargyl or benzyl radical, or xe2x80x94NR3R4, R3 and R4 possibly representing a methyl radical or forming, together with the nitrogen atom to which they are attached, a saturated or unsaturated 4- or 5-membered heterocycle which can also contain another hetero atom chosen from nitrogen, oxygen and sulphur, R2 is a hydrogen atom or a methyl or ethyl radical, and the bond - - -  represents a single bond or a double bond, as well as the salts thereof.
The A-group streptogramin compounds which may be combined therewith can also be chosen from semisynthetic compounds of formula (xcex2): 
wherein:
R1 is chosen from halogen atoms and azido and thiocyanato radicals;
R2 is chosen from hydrogen atoms and methyl and ethyl radicals;
R3 is chosen from hydrogen atoms and aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic and heterocyclylaliphatic ester residues which may be substituted or unsubstituted; and
the bond - - -  represents a single bond (27R stereochemistry) or a double bond; and the salts thereof.
According to one embodiment, the compounds of formula (xcex2) that can be combined therewith include those wherein the ester residue R3 is chosen from:
Rxe2x80x23xe2x80x94COxe2x80x94 radicals, wherein Rxe2x80x23 is chosen from:
phenyl and phenylalkyl radicals, which are unsubstituted or substituted on the phenyl radical with one or more radicals chosen from:
alkyl radicals, optionally bearing a radical NRxe2x80x3Rxe2x80x2xe2x80x3 wherein the radicals Rxe2x80x3 and Rxe2x80x2xe2x80x3, which may be identical or different, are chosen from:
a hydrogen atom and alkyl radicals which can form, together with the nitrogen atom to which they are attached, saturated and unsaturated 3- to 8-membered heterocyclyl radicals, optionally comprising at least one additional hetero atom chosen from oxygen, sulphur, and nitrogen, it being possible for the heterocycle itself to be substituted with one or more radicals chosen from saturated and unsaturated 3- to 8-membered alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxycarbonylalkyl, aryl, heterocyclyl, heterocyclylalkyl, and xe2x80x94CH2xe2x80x94COxe2x80x94NRxe2x80x3Rxe2x80x2xe2x80x3;
or, alternatively,
Rxe2x80x3 and Rxe2x80x2xe2x80x3 are chosen from:
saturated and unsaturated 3- to 8-membered hydroxyalkyl, phenyl, and heterocyclylalkyl radicals, a radical xe2x80x94COxe2x80x94NRxe2x80x3Rxe2x80x2xe2x80x3 wherein NRxe2x80x3Rxe2x80x2xe2x80x3 is defined as above, and alkyl and acyl radicals, substituted with NRxe2x80x3Rxe2x80x2xe2x80x3 defined as above;
or, alternatively,
Rxe2x80x23 is chosen from phenyl and phenylalkyl radicals which are substituted on the phenyl radical with one or more radicals chosen from:
alkyl, which is unsubstituted or substituted with alkyloxy and alkylthio radicals, themselves optionally bearing a carboxyl radical or a radical NRxe2x80x3Rxe2x80x2xe2x80x3 defined as above, or chosen from acyloxy which can be substituted with NRxe2x80x3Rxe2x80x2xe2x80x3 defined as above;
or, alternatively,
Rxe2x80x23 is chosen from alkyl and cycloalkyl radicals which are unsubstituted or substituted with at least one radical chosen from carboxyl, carboxyalkyldisulphanyl, NRxe2x80x3Rxe2x80x2xe2x80x3, xe2x80x94CH2xe2x80x94NRxe2x80x3Rxe2x80x2xe2x80x3, xe2x80x94COxe2x80x94NRxe2x80x3Rxe2x80x2xe2x80x3, alkyloxycarbonyl, alkyloxy, and alkyldisulphanyl radicals, which are unsubstituted or substituted with at least one radical chosen from:
NRxe2x80x3Rxe2x80x2xe2x80x3 and xe2x80x94COxe2x80x94NRxe2x80x3Rxe2x80x2xe2x80x3, wherein NRxe2x80x3Rxe2x80x2xe2x80x3 is defined as above;
or, alternatively,
Rxe2x80x23 is chosen from saturated and unsaturated 3- to 8-membered heterocyclyl radicals which are unsubstituted or substituted with at least one radical chosen from alkyl and acyl radicals, both of which are unsubstituted or substituted with NRxe2x80x3Rxe2x80x2xe2x80x3.
It is understood in the formula (xcex2) above that, when R1 is halogen, it can be chosen from chlorine, bromine, fluorine and iodine, and that the combinations of the compounds according to the invention with the A-group streptogramins also fall within the context of the present invention.
The streptogramin compounds according to the invention have been shown to be active in vitro on Staphylococcus aureus 209P at concentrations ranging from 0.25 xcexcg/ml to 32 xcexcg/ml when combined with an A-group streptogramin compound, such as pristinamycin IIB, and at concentrations ranging from 0.5 xcexcg/ml to 32 xcexcg/ml on Staphylococcus aureus Schiclia (meticillin-resistant) combined with pristinamycin IIB; in vivo, they synergize the antimicrobial activity of pristinamycin IIB on experimental infections of mice with Staphylococcus aureus IP8203 at doses ranging from 10 mg/kg to 150 mg/kg subcutaneously (CD50), and orally at doses ranging from 24 mg/kg to 150 mg/kg (CD50) (30/70 combinations).
The compounds according to the invention may be useful on account of their low toxicity. None of the compounds showed any toxicity at a dose of 150 mg/kg orally (2 administrations).
Among these compounds, the compounds of formula (I) wherein:
R is chosen from xe2x80x94NR1R2 and xe2x80x94SR3, wherein:
R1 and R2, which may be identical or different, are independently chosen from hydrogen and the radicals:
alkyl (1 to 8 carbons), unsubstituted or substituted with hydroxyl;
alkenyl (3 to 8 carbons);
cycloalkyl (3 to 8 carbons);
alkyloxy (1 to 8 carbons);
dialkylamino;
phenylalkyl, which is unsubstituted or substituted with one or more substitutents chosen from halogen atoms and alkyl, hydroxyalkyl, alkyloxy, and dialkylamino radicals;
saturated and unsaturated heterocyclylalkyl radicals (3- to 8-membered) containing one or more hetero atoms chosen from nitrogen, sulphur, and oxygen; and dialkylaminoalkyl;
or, alternatively,
R1 and R2, together with the nitrogen atom to which they are attached, form a ring chosen from 3- to 12-membered, saturated, partially saturated and unsaturated, monocyclic and polycyclic heterocycles, optionally containing at least one additional hetero atom chosen from oxygen, sulphur, and nitrogen, which heterocycle is unsubstituted or substituted with one or more radicals chosen from:
hydroxyl;
alkyl;
phenyl, which is unsubstituted or substituted with a halogen atom;
phenylalkyl;
hydroxyalkyl;
acyl;
alkyloxycarbonyl; and
heterocyclyl and heterocyclylcarbonyl radicals, wherein the heterocyclyl portion (4- to 6-membered) is saturated or unsaturated and contains one or more hetero atoms chosen from oxygen, sulphur, and nitrogen;
R3 is chosen from alkyl radicals (1 to 8 carbons), which are substituted with a radical xe2x80x94NR1R2 wherein:
R1 and R2, which may be identical or different, are chosen from alkyl radicals, or form, together with the nitrogen atom to which they are attached, a heterocycle as defined above;
or, alternatively,
R3 is chosen from 3- to 7-membered, saturated and unsaturated, monocyclic and polycyclic heterocyclyl and heterocyclylmethyl radicals, optionally containing at least one additional hetero atom chosen from oxygen, sulphur, and nitrogen, and which are unsubstituted or substituted with one or more alkyl radicals, 
xe2x80x83is an unsaturated ring residue which is unsubstituted at 5xcex3: 
xe2x80x83or a saturated ring residue which is substituted at 5xcex3 with a fluoro radical: 
Ra is an ethyl radical, and
Rb, Rc, and Rd have the definitions below:
1) Rb and Rc are both a hydrogen atom, and Rd is chosen from methylamino and dimethylamino radicals;
2) Rb is a hydrogen atom, Rc is chosen from hydrogen and chlorine atoms, and Rd is a radical xe2x80x94NMexe2x80x94Rxe2x80x2xe2x80x3, wherein Rxe2x80x2xe2x80x3 is chosen from:
alkenyl radicals (2 to 8 carbons), heterocyclylmethyl radicals, and xe2x80x94COORxe2x80x2e, -wherein Rxe2x80x2e is chosen from:
alkyl (1 to 6 carbons), alkenyl (2 to 6 carbons), phenyl, and tolyl radicals;
3) Rb is a hydrogen atom, Rd is chosen from xe2x80x94NHCH3 and xe2x80x94N(CH3)2 radicals, and Rc is chlorine;
are included within one embodiment of the invention.
In addition, by way of example, the following compounds may be mentioned:
5xcex4-(1-morpholino)methyl-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-[N-methyl-N-2-(1,3-dioxolanyl)methyl]aminomethyl-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-morpholinomethyl-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-morpholinomethyl-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydro-4xcex5-chloropristinamycin IE; and
5xcex4-[bis(2-methoxyethyl)aminomethyl]-5xcex4,5xcex3-dehydropristinamycin IE.
According to one embodiment of the invention, the compounds cited in the examples are suitable, as are the following listed streptogramin compounds:
4xcex5-chloro-5xcex4-(diethylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(diethylaminoethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(diethylaminoethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(3-diethylaminopropylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(3-diethylaminopropylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(3-diethylaminopropylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(3-diethylaminopropylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(dimethylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(dimethylaminoethylthiomethyl)-5;,5xcex3-dehydropristinamycin IE;
5xcex4-(dimethylaminoethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(dimethylaminoethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(3-piperidinopropyl)thiomethyl-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(1-methyl-2-imidazolylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(1-methyl-2-imidazolylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(1-methyl-2-imidazolylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(morpholinoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(morpholinoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(morpholinoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(morpholinoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(2-piperidinoethyl)thiomethyl-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(2-piperidinoethyl)thiomethyl-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(2-piperidinoethyl)thiomethyl-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(3-piperidinopropyl)thiomethyl-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(3-piperidinopropyl)thiomethyl-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(3-piperidinopropyl)thiomethyl-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(4-pyridylmethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(4-pyridylmethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(4-pyridylmethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(3-pyridylmethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(3-pyridylmethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(3-pyridylmethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(2-pyridylmethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(2-pyridylmethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(2-pyridylmethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(2-pyridylmethylthiomethyl)-4"xgr"-methylamino-4"xgr"-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-{[2-(4-methylpiperazin-1-yl)ethyl]thiomethyl}-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-{[2-(4-methylpiperazin-1-yl)ethyl]thiomethyl}-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-{[2-(4-methylpiperazin-1-yl)ethyl]thiomethyl}-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-{[2-(4-methylpiperazin-1-yl)ethyl]thiomethyl}-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(butoxycarbonylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(butoxycarbonylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(butoxycarbonylaminomethylthioethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(butoxycarbonylaminoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(aminoethylhiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(aminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(aminomethylthioethyl)-4xcex6-methyamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-(chloro-5xcex4-(aminoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(pyrrolidinoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(pyrrolidinoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(pyrrolidinoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(pyrrolidinoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(diisopropylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(diisopropylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(diisopropylaminoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(diisopropylaminoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(N-ethyl-N-methylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(N-ethyl-N-methylaminoethylthiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-(N-ethyl-N-methylaminoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-(N-ethyl-N-methylaminoethylthiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-((2R)-3-diethylaminopropyl-2-thiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-((2R)-3-diethylaminopropyl-2-thiomethyl )-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-((2R)-3-diethylaminopropyl-2-thiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-((2R)-3-diethylaminopropyl-2-thiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-((2S)-3-diethylaminopropyl-2-thiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
4xcex5-chloro-5xcex4-((2S)-3-diethylaminopropyl-2-thiomethyl)-5xcex4,5xcex3-dehydropristinamycin IE;
5xcex4-((2S)-3-diethylaminopropyl-2-thiomethyl-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE; and
4xcex5-chloro-5xcex4-((2S)-3-diethylaminopropyl-2-thiomethyl)-4xcex6-methylamino-4xcex6-dedimethylamino-5xcex4,5xcex3-dehydropristinamycin IE.
The streptogramin compounds of formula (xcex1) are described, along with their preparation, in international patent application WO 99/05165, the disclosure of which is incorporated herein by reference.
The streptogramin compounds of formula (xcex2), described in French patent application FR 99/08375, the disclosure of which is incorporated herein by reference, are prepared by halogenation, by conversion into an azide or by conversion into a thiocyanate, of a streptogramin compound of formula (xcex3): 
wherein R2 is defined as above, the - - -  bond represents a single bond (27R stereochemistry) or a double bond, and wherein the hydroxyl function in position 14 has been protected beforehand, followed by removal of the protecting radical and, where appropriate, in order to obtain a compound or formula (xcex2) wherein R3 is other than a hydrogen atom, by introduction of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, or heterocyclylaliphatic ester residue which may be substituted (R3) according to the usual methods which do not adversely affect the rest of the molecule.
The halogenation reactions, conversion into an azide, or conversion into a thiocyanate can be performed in the presence of an aminosulphur trifluoride such as, for example, diethylaminosulphur trifluoride, bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor(copyright)), or morpholinosulphur trifluoride, or, alternatively, in the presence of sodium tetrafluoride, using a reagent such as a tetraalkylammonium, for example, tetramethylammonium, tetraethylammonium, tetrapropylammonium, or tetrabutylammonium, trialkylbenzylammonium or trialkylphenylammonium halide, azide, or thiocyanate, or using an alkali metal halide, azide or thiocyanate optionally supplemented with crown ether. The reaction is performed in a chlorinated organic solvent such as, for example, dichloromethane, dichloroethane, or chloroform, or in an ether such as tetrahydrofuran, at a temperature ranging from xe2x88x9278xc2x0 C. to 40xc2x0 C., optionally under argon or nitrogen. The use of the hydroxyl compound of (16S) configuration gives the compound of (16R) configuration. The protection and deprotection of the hydroxyl radical in position 14 is performed according to the usual methods which do not adversely affect the rest of the molecule (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd edition), Wileyxe2x80x94Interscience (1991), the disclosure of which is incorporated herein by reference).
In order to prepare a compound of formula (xcex2) wherein R3 is an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, or heterocyclylaliphatic ester which may be substituted, the esterification is performed by reacting the acid or a reactive derivative of the acid such as, for example, acid chloride, reactive ester, or anhydride, in the presence or absence of a coupling agent such as, for example, a carbodiimide, for example, dicyclohexylcarbodiimide, and a tertiary amine such as, for example, a trialkylamine, for example triethylamine, diisopropylethylamine, pyridine, or a derivative of any of the foregoing, and optionally a catalyst such as 4-N-dimethylaminopyridine, at a temperature ranging from 40xc2x0 C. to +80xc2x0 C., in an organic solvent such as an amide, for example, dimethylformamide or N-methyl-2-pyrrolidinone, pyridine, a halogenated solvent, for example, dichloromethane, dichloroethane, or chloroform, or an ether, such as tetrahydrofuran, dioxane, or dimethoxyethane. The functions which may interfere with the reaction are protected beforehand.
The following nonlimiting examples illustrate the present invention.
In the examples which follow, the NMR spectra were acquired in deuterochloroform, the nomenclature used is that of J. O. Anteunis et al., Eur. Biochem., 58, 259 (1975), the disclosure of which is incorporated herein by reference.
The column chromatographies were performed, except where otherwise mentioned, under atmospheric pressure using a 0.063-0.02 mm silica. In a few specific cases, the purifications were performed by flash chromatography using a 0.04-0.063 mm silica, or by high performance liquid chromatography (HPLC) on C8 or C18 grafted silica. As the chromatography proceeded, the fractions were analysed by thin layer chromatography (TLC) on Merck 60F254 silica plates, or by analytical HPLC. The fractions corresponding to the same Rf or to the same retention time were combined and then concentrated to dryness, under reduced pressure (30-45xc2x0 C.; 2.7 kPa). The products thus obtained were analysed by the usual spectroscopic techniques (NMR; IR; MS), which allowed the expected products to be identified.